PositionpaperonpreferreddosageformstobeincludedinaModel EssentialMedicinesListforChildren

Introduction Thereportonthe4thModelListofEssentialDrugsincludesguidelinesfortheselectionof pharmaceuticaldosageforms.1Undertheheadingofcriteriafortheselectionofessential drugs,thereportstatesthateachselecteddrugmustbeavailableinaforminwhich adequatequality,includingbioavailability,canbeassured.Otherissuesidentifiedwere stabilityunderanticipatedconditionsofstorageanduse,therelativecostofdifferent dosageforms,generalutilityandwideavailabilityinternationally.Unfortunately,the reportstates,Specificpaediatricdosagesandformulationsareincludedinthelistonly whenindicatedbyspecialcircumstances. Thepurposesofthesepolicystatementsareto: 1. Identifywhichfactorsshouldbetakenintoaccountwhenmakingachoiceof paediatricdosageformstobeincludedinaModelEssentialMedicinesListfor Children. 2. Reviewtheevidenceforthesuitabilityofdifferentformulationsforpaediatric medicines,consideringsuchfactorsashavebeenidentified,includingissuesof dosingaccuracy,palatability,stability,easeoftransportandstorage. 3. Recommendpreferableformulationsfordifferentagegroupsofchildren,including neonatespremature&fullterm,younginfantsandolderchildren. Thesepolicystatementsareprimarilyextrapolatedfromclinicalpracticeandavailable publishedinformationincludingtheEuropeanMedicineAgencyCommitteeformedicinal productsforHumanuse,reflectionpaper:Formulationofchoiceforthepaediatric population,dated28July2006. Overarchingstatement Liquidformulationscanoffersuperiorpalatabilitytodissolvedsolidtablets,intendedfor swallowingwhole,howeverthetransportation,storageandtemperaturemonitoring requiredforliquidformulationsrenderthisbulkydosageformasapotentialbarrierfortheir useinregionsoftheworldunderstressorharshlivingconditions. Policystatement:Thestabilityofandhavingaccesstopaediatricmedicinesisparamount. Wheneverpossible,everyeffortmustbeextendedtooptimizetheirpalatabilityofpaediatric medicines.Theidealpaediatricformulationcharacteristicslistedbelowaredesirablewhen thechemicalstabilityorproductavailabilityallows.Whenthestabilityorproduct availabilitydoesnotpermitoneofthefollowingsuggestedcharacteristics,thisshouldnot preventpediatricpatientsfromaccessingmedications.
WorldHealthOrganization.Theuseofessentialdrugs.SecondreportoftheWHOExpert Committee.TechnicalReportSeries722,1985.
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 Policystatement:Formulationsshouldcontainonlyexcipientsknowntobesafeforall paediatricagegroups.Thisistoensureflexibilityinmedicationsupply. Oralformulations Policystatement:Thepreferredoralformulationisthetabletasitisthemosteasilystored andisstableoverthewidestrangeofenvironmentalconditions.Appropriatelyformulated oralTablets(seebelow)canmeettheneedsofmostpaediatricpatientswhenusedproperly inprovidingpointofcare,aspatientspecificsolutions,suspensionsorslurriescanbe preparedatthetimeofadministration.Chewinggum,capsules,oralpowder,orodispersible andoromucosaldosageformulationsareacceptable,butrequireagespecificdosageforms. Intheabsenceofanabilitytomodifythedoseamountfortheselatterdoseforms(e.g., cuttingthepatchformulationtoaspecificdose,etc.)thesefixeddoseformulationsarenot practicalwhenconsideringdosingaccuracy,palatability,stability,easeoftransportand storage. Factorstoconsiderinchoosingatabletformulation: o Tabletsshouldbescoredsotheymaybeeasysplit(withfingers)accurately accommodateaquarterdose. o Dosagesshouldbestandardizedusingincrementsofonequartertabletformost drugswithawidetherapeuticwindow.Manydosesmaybeadaptedfromusing atabletthatcanbedividedinfoursections,withaquartertabletprovidingadose fora10kgchild. o Tabletsshoulddisintegrateeasilyinwatertoenablepreparationofapointof care,patientspecificsolutions,suspensionsorslurriesatthetimeof administration(e.g.,dissolveonefourthofatabletin1.25to2.5mLofwaterto administeroneeighthofatablet.Thisaccommodatesamedicationnavepatient totakeamedicationbysimplymixingittowaterpriortoadministration.In applyingsuchextemporaneouspointofcaredosingitishighlydesirablefor calibratedmeasuringspoonsbeavailableandusedtoensuredosageaccuracyof thespecificsolution/suspension/slurryatthetimeofadministration. o Waterusedtosuspendordilutetabletsshouldbefreeofcontaminantsand pathogens. o Excipientsshouldbeinert,glutenfree,lactosefreeandfreefromdyesthatmay causeallergicreactionsorsideeffectssuchastartrazineandreddyes. o Forpatientsafety,tabletsshouldbeidentifiablebydifferentcoloursorbranding imprintsormarkings.Theuseofuniqueimprintcodeontabletformsshouldbe mandated. o Chewableororallydisintegratingtabletsarepreferredtooralsuspensionswhena flavourisrequiredtomaskbadtastingmedication.Chewableororally disintegratingtabletsshoulddisintegrateinwatereasilytoenablethepreparation ofpointofcare,patientspecificsolutions/suspensions/slurriesatthetimeof administration. o Slowreleaseformulationsshouldbeavoidedunlessabsolutelyclinicallyrequired orthatcanbecutorcrushedtoprovidebetterdosingversatility.
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Policystatement:Liquidformulationsshouldberestrictedtolesspalatablemedicationsthat preventchildrenfromachievingatherapeuticbenefit.Costeffectivechewableororally disintegratingtabletsarepreferredtooralsuspensions/liquidswhenaflavourisrequiredto maskbadtestingmedications.Chewableororallydisintegratingtabletsshoulddisintegrate inwatereasilytoenableapointofcare,patientspecificsolutions,suspensionsorslurriesat thetimeofadministration.Cylindricalmeasuringspoonsororaldosingsyringesshouldbe providedtoensuredosageaccuracywhenaliquidformulationisdispensed. Factorstoconsiderinchoosingaliquidformulation: - Thedosevolumeshouldbe(lessthan)5mLforchildrenunder5yearsand (lessthan)10mLforchildren5yearsorolder. - Oralsolution(oraldrops)ofverysmalldosevolumesisacceptableifthe manufacturerprovidesrecommendationsfordilutioninbeveragetoimprove palatability. - Suspensionsshouldbefreeofexcipient(s)thatmaycauseundesirableeffects includingdiarrheawithsorbitolorxylitol. Waterusedtoreconstitutesuspensionsshouldbefreeofcontaminantsand pathogens. - Flavoursselectedshouldhavebeenshowntoeffectivelymaskpoortaste withoutriskofadverseeffects. - Affordveryversatiletemperaturestoragerangefocusingonroom temperature&atemperaturerangethataccommodatesexpected environmentaltemperatureswithintheworldsmanytemperentzones. - Drypowdertobereconstitutedatpointofcare Parenteralformulations Factorsthatshouldbeconsideredinforparenteralformulationsinclude: - Preferablyusepreservativefree,singledoseorsafepreservativeavoidexcipientthat maybeharmfultopaediatricpatients,e.g.,neonatesandbenzoylalcohol,propylene glycol... - preferenceshouldbegiventolatexfreerubberstoppercontainers,portofIVtubing andbags; - formulationshouldbeavailableinaprotectedfromlightcontainers; - preferredstorageatroomtemperature; - tearofflabelfromoriginalvialtolabelsyringesforpatientsafety. Injectables Policystatement:Theintravenousandsubcutaneousroutesarethepreferredroutesfor parenteraladministrationasareapplicabletoallagegroups. Inchoosinganintravenousformulationthefollowingshouldbeconsidered: o Manufacturersshouldprovidedilutioninformationtoenabletohavethe medicationbeadministeredviacentralorperipheralveininchildren.
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o o

Theproductshouldbecompatiblewithglucose5%&10%,sodiumchloride 0.45%and0.9%andacombinationofglucoseandsalineaswellasinthe presenceofimportantprimaryelectrolytes,e.g.,potassium,chloride,calcium andpossiblymagnesium. Themaximumrateofadministrationshouldbestatedinmg/Kg/minuteor microgram/Kg/minute. IsoosmoticandpHneutralpreparationsarepreferredtolimitthoserisks associatedwithinfiltrationtoxicity,thrombophlebitisandhemolysis.

InchoosingaSubcutaneousformulationthefollowingshouldbeconsidered: o ThemedicationshouldbeatornearphysiologicalpHof7.4 o Themedicationdoseshouldbecontainedwithinasmallvolume. Policystatement:Intradermalinjectionshouldberestrictedtomedicationsortestswhere thereisnoothermethodofadministration(e.g.,tuberculintest). Policystatement:Wheneverpossible,theintramuscularrouteofdrugadministration shouldbeavoided.Althoughundesirable,intramusculardrugadministrationmaybe appropriateforaonetimedosetreatmentorinthosepatientswithnovenousaccessandno availablesurgicalexpertiseforeffectivelineplacement.Further,multipleintramuscular dosesareproblematicfromasitestandpointandpatienttolerability/compliance.Inthe absenceofabsolutenecessityasnotedabove,theintramuscularformulationisusuallynot practicalinsickneonates. Policystatement:Nasaldrops,spraysandpowdersareacceptabledosageformifeachare nonirritatinganddonotaffectmucosalfunction.Penetrationenhancersshouldbeshownto besafeandeffectiveinthetargetpopulation.Theseformulationsmaybeapplicabletoallage groups. Policystatement:Rectalformulationsmaybeapplicableinallagegroups.However,this modeofadministrationisnotwidelyacceptedbypaediatricpatientsandisthusnot preferredunlessitistobeusedinclinicalsituationswhereoralorintravenous administrationisnotpractical(e.g.,treatmentofnauseaandvomiting).Thesizeofthe suppositoryshouldberelatedtothepatientssizeandshouldbeabletosplittoallowfor partialaccuratedosages,ifnecessary. Policystatement:Topicalagentsthatarecommonlyusedinadultsmaybeusedinchildren ofmostagegroups.However,increasedskinsurfaceareaandenhanceddermalpenetration ofinfantsandneonatesmustbeconsideredwhenselectinganddosingtopicalmedications. Transdermalpatchesshouldonlybeusedinneonatesifthereisagespecificsupportingdata available. Policystatement:Pulmonaryagentscanbeusedsafelyinchildren;nebulizersmaybeused inallpaediatricagegroupsbutmayrequirespecializedequipment.Metereddoseinhalers withappropriateagespacersmaybeusedinallagegroupsexceptneonates.Drypowder inhalersshouldberestrictedtochildrengreaterthan5yearsofage.
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Contributorstothispositionpaper:RegisVaillancourt(Canada)DavidKnoppert (Canada),MichaelReed(US),SandraBenavides(US),JoyceTotton(Canada),DavidHoff (US),BradyMoffett(US),KelleyNorris(US),). 20April2007 Bibliography

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WorldHealthOrganization.Theuseofessentialdrugs.SecondreportoftheWHOExpert Committee.TechnicalReportSeries722,1985. BritishNationalFormularyforChildren,2006. GuidanceforIndustryGeneralConsiderationsforPediatricPharmacokineticStudiesfor DrugsandBiologicalproducts,DraftGuidance,USFDA,10November1998. Modifiedafter:YaffeSJandArandaJV.PediatricPharmacologyTherapeuticPrinciplesin Practice.Saunders,1992 EuropeanMedicinesAgency.ReflectionPaper:FormulationsofChoiceforthePaediatric Population,London,28July2006. TaketomoCK,HoddingJH,KrausDM.PediatricDosageHandbook,13thEdition,LexiComp, 2006. CalleG,LagomarsimoE.EvaluationofPreferredDosageFormsin338ArgentinianPaediatric Outpatients(personalcommunication). Personalexperience

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